3,5,3˜5˜-Tetraiodothyronine (thyroxine, or T4) 3,5,3˜-Triiodothyronine (T3) •Fig. 38.11 Structureofthyroidhormones,whichareiodothyronines.
transport systems. They are stored extracellularly in the thyroid as an integral part of the glycoprotein molecule thyroglobulin. Thyroid hormones are sparingly soluble in blood and aqueous fluids and are transported in blood that is bound (>99%) to serum-binding proteins. A major transport protein is thyroid hormone–binding globulin. Thyroid hormones have long half-lives (7 days for thyroxine; 18 hours for triiodothyronine). Thyroid hormones are similar to steroid hormones in that the thyroid hormone receptor is intracellular and acts as a transcription factor. In fact, the thyroid hormone receptor belongs to the same gene family that includes steroid hormone receptors and vitamin D receptor. Thyroid hormones can be administered orally; the amount absorbed intact is sufficient for this to be an effective mode of therapy.
Transport of Hormones in the Circulation
A significant fraction of steroid and thyroid hormones is transported in blood that is bound to plasma proteins that are produced in a regulated manner by the liver. Protein and polypeptide hormones are generally transported free in blood. The concentrations of bound hormone, free hormone, and plasma transport protein are in equilibrium. If free hormone levels drop, hormone will be released from the transport proteins. This relationship may be expressed as follows:
Equation 38.1 where [H] = concentration of free hormone, [P] = concentration of plasma transport protein, [HP] = concentration of bound hormone, and K = the dissociation constant.
Free hormone is the biologically active form for action on the target organ, feedback control, and clearance by cellular uptake and metabolism. As a consequence, when hormonal status is evaluated, sometimes free hormone levels must be determined in addition to total hormone levels. This is particularly important because hormone transport proteins themselves are regulated by altered endocrine and disease states.
Protein binding serves several purposes. It prolongs the circulating half-life of the hormone. Many hormones cross cell membranes readily and would either enter cells or be excreted by the kidneys if they were not protein bound. The bound hormone represents a reservoir of hormone and, as such, can serve to buffer acute changes in hormone secretion. Some hormones, such as steroids, are sparingly soluble in blood, and protein binding facilitates their transport.
Cellular Responses to Hormones
Hormones are also referred to as ligands, in the context of ligand-receptor binding, and as agonists, in that their binding to the receptor is transduced into a cellular response. Receptor antagonists typically bind to a receptor and lock it in an inactive state, in which the receptor is unable to induce a cellular response. Loss or inactivation of a receptor results in hormonal resistance. Constitutive activation of a receptor leads to unregulated, hormone-independent activation of cellular processes.
Hormones regulate essentially every major aspect of cellular function in every organ system. Hormones control the growth of cells, ultimately determining their size and competency for cell division. Hormones regulate the differentiation of cells and their ability to survive or to undergo programmed cell death. They influence cellular metabolism, the ionic composition of body fluids, and cell membrane potential. Hormones orchestrate several complex cytoskeleton-associated events, including cell shape, migration, division, exocytosis, recycling/endocytosis, and cell-cell and cell-matrix adhesion. Hormones regulate the expression and function of cytosolic and membrane proteins, and a specific hormone may determine the level of its own receptor or the receptors for other hormones.